SCIENTIFIC OPINION. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) 2, 3. European Food Safety Authority (EFSA), Parma, Italy

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1 SCIENTIFIC OPINION Scientific Opinion on the appropriateness of the food azo-colours Tartrazine (E 102), Sunset Yellow FCF (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E 124), Allura Red AC (E 129), Brilliant Black BN (E 151), Brown FK (E 154), Brown HT (E 155) and Litholrubine BK (E 180) for inclusion in the list of food ingredients set up in Annex IIIa of Directive 2000/13/EC 1 EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) 2, 3 European Food Safety Authority (EFSA), Parma, Italy ABSTRACT Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to provide a scientific opinion on the appropriateness of the food azo-colours Tartrazine (E 102), Sunset Yellow (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E 124), Allura Red AC (E 129), Brilliant Black BN (E 151), Brown FK (E 154), Brown HT (E 155) and Litholrubine BK (E 180) for inclusion in the list of food ingredients set up in Annex IIIa of Directive 2000/13/EC. This opinion addresses the potential of food azo-colours to cause intolerance and/or allergic reactions in humans after oral exposure. There is a shortage of large, well-controlled intervention studies with defined criteria following double-blind placebo-controlled food challenge principles. In addition, most of the studies have been conducted on selected patients. The frequency of Tartrazine intolerance has been estimated to be <1 % in subjects with food-induced urticaria and angioedema. Only few cases of intolerance reactions to Tartrazine and Ponceau 4R, and to a lesser extent to Sunset Yellow FCF and Amaranth, in sensitive individuals have been reported. These reactions include urticaria, angioedema, wheezing, and leukoclastic vasculitis. No data on sensitivity to Brown FK, Brown HT, Litholrubine BK, Brilliant Black BN, Carmoisine, and Allura Red AC are available, and no well-documented cases of intolerance reactions after oral exposure have been reported. Only few cases of intolerance reactions to colour mixtures including azodyes have been reported. Intolerance reactions include urticaria, periorbital oedema, facial flushing, as well as higher hyperactivity scores in children. The Panel concludes that it is unlikely that oral consumption of the food colours under consideration, either individually or in combination, would trigger severe adverse reactions in human subjects at the current levels of use. European Food Safety Authority, 2010 KEY WORDS Azo-colours, Tartrazine, Sunset Yellow, Carmoisine, Amaranth, Ponceau, Allura Red, Brilliant Black, Brown, Litholrubine, food allergy. 1 On request from the European Commission, Question No EFSA-Q , adopted on 10 September Panel members: Carlo Agostoni, Jean-Louis Bresson, Susan Fairweather-Tait, Albert Flynn, Ines Golly, Hannu Korhonen, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Monika Neuhäuser-Berthold, Hildegard Przyrembel, Seppo Salminen, Yolanda Sanz, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Daniel Tomé, Hendrik van Loveren and Hans Verhagen. Correspondence: nda@efsa.europa.eu Suggested citation: EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the appropriateness of the food azo-colours Tartrazine (E 102), Sunset Yellow FCF (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E 124), Allura Red AC (E 129), Brilliant Black BN (E 151), Brown FK (E 154), Brown HT (E 155) and Litholrubine BK (E 180) for inclusion in the list of food ingredients set up in Annex IIIa of Directive 2000/13/EC. EFSA Journal 2010;8(10):1778. [11 pp.]. doi: /j.efsa Available online: European Food Safety Authority,

2 SUMMARY Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to provide a scientific opinion, in the light of the most recent scientific evidence, on the appropriateness of the food azo-colours Tartrazine (E 102), Sunset Yellow (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E 124), Allura Red AC (E 129), Brilliant Black BN (E 151), Brown FK (E 154), Brown HT (E 155) and Litholrubine BK (E 180) for inclusion in the list of food ingredients set up in Annex IIIa of Directive 2000/13/EC, as amended. This opinion addresses the potential of individual food azo-colours, or their combinations, to cause intolerance and/or allergic reactions in humans after oral exposure, including the nature and prevalence of such adverse reactions. The potential of azo-colours to cause sensitisation following skin exposure is not addressed in this opinion. Since the description of adverse reactions to the synthetic food colour Tartrazine over 50 years ago, a number of case reports have been published describing intolerance reactions. However, most published reports have been inadequately controlled, non-blinded and performed without an appropriate follow-up period to assess the effects of an exclusion diet, and therefore, it is uncertain whether the reported adverse reactions were indeed due to oral exposure to Tartrazine. There is a shortage of large, well-controlled intervention studies with defined criteria following double-blind placebo-controlled food challenge (DBPCFC) principles which assessed the (adverse) effects of oral consumption of individual food azo-colours in humans. In addition, most of the studies designed to estimate the incidence of azo-colour intolerance have been conducted on selected patients with intolerance reactions in hospital settings, and no data are available with respect to the prevalence of intolerance to individual azo-colours in a non-selected general population. The frequency of Tartrazine intolerance has been estimated to be <1 % in subjects with food-induced urticaria and angioedema. Only few cases of intolerance reactions to Tartrazine and Ponceau 4R, and to a lesser extent to Sunset Yellow FCF and Amaranth, in sensitive individuals have been reported following DBPCFC procedures after exclusion diets. These reactions include urticaria, angioedema, wheezing, and leukoclastic vasculitis. Intolerance reactions to Tartrazine have been observed at doses within the ADI (7.5 mg/kg bw/day), whereas the challenge doses of Ponceau 4R used in two-well documented cases of intolerance reactions to this colour were four to 10 times the ADI (0.7 mg/kg bw/day). No data on sensitivity to Brown FK, Brown HT, Litholrubine BK, Brilliant Black BN, Carmoisine, and Allura Red AC are available, and no well-documented cases of intolerance reactions after oral exposure have been reported. However, the absence of data on adverse clinical reactions after oral exposure could be due to the lack of clinical awareness of this possibility and subsequent underreporting. Only few cases of intolerance reactions to colour mixtures including azo-dyes have been reported in sensitive individuals following DBPCFC procedures after exclusion diets. Intolerance reactions include urticaria, periorbital oedema, facial flushing, as well as higher hyperactivity scores in children. The Panel concludes that it is unlikely that oral consumption of the food colours under consideration, either individually or in combination, would trigger severe adverse reactions in human subjects at the current levels of use. 2

3 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 3 Background as provided by the European Commission... 4 Terms of reference as provided by the European Commission... 4 Assessment Introduction Evidence for adverse reactions to individual food colours Evidence for adverse reactions to colour mixtures... 7 Conclusions... 8 References... 8 Glossary / Abbreviations

4 BACKGROUND AS PROVIDED BY THE EUROPEAN COMMISSION Annex IIIa of Directive 2000/13/EC, as amended, establishes a list of food ingredients that are known to trigger allergies or intolerances. The aforementioned Directive states that whenever the listed ingredients are used in the production of foodstuffs they must be labelled. Article 6, paragraph 11 of the same Directive requests that the list in Annex IIIa shall be systematically re-examined and, where necessary, updated on the basis of the most recent scientific knowledge. Furthermore, paragraph 11 states that Annex IIIa may be amended, in compliance with the procedure referred to in Article 20 (2), on the basis of a scientific opinion of the European Food Safety Authority. Directive 94/36/EC on colours for use in foodstuffs authorises the use of Tartrazine (E 102), Sunset yellow (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E 124), Allura Red (E 129), Brilliant Black BN (E151), Brown FK (E 154), Brown HT (E 155) and Litholrubine BK (E 180) in certain categories of foodstuffs listed in Annex IV and Annex V, part 2, and sets the maximum level of use. These colours have been re-evaluated by EFSA for their safety in the frame of re-evaluation of all food additives. In the context of the ongoing co-decision procedure on the Food Improvement Agents Package, which includes a proposal for a Regulation on food additives, the Commission has been asked by the European Parliament and the Council to consider the inclusion in the list of food ingredients of the above-mentioned azo-colours. Therefore, in accordance with Article 6, paragraph 11 of Directive 2000/13/EC, the Commission requests EFSA to determine whether the most recent scientific knowledge provides evidence to support the inclusion of those ingredients in the list in Annex IIIa of Directive 2000/13/EC, as amended by Directives 2003/89/EC, 2006/142/EC and 2007/68/EC. TERMS OF REFERENCE AS PROVIDED BY THE EUROPEAN COMMISSION In accordance with Article 29 (1) (a) of Regulation (EC) N 178/2002, the European Commission requests the European Food Safety Authority to provide a scientific opinion, in the light of the most recent scientific evidence, on the appropriateness for inclusion in the list of food ingredients set up in Annex IIIa of Directive 2000/13/EC, as amended, of the following food colours: Tartrazine (E 102), Sunset yellow (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E 124), Allura Red (E 129), Brilliant Black BN (E 151), Brown FK (E 154), Brown HT (E 155) and Litholrubine BK (E 180). 4

5 ASSESSMENT 1. Introduction Synthetic azo-dyes account for approximately 70 % of all dyes used in food manufacture and use of yellow/red dyes is more common than use of blue/brown dyes. All dyes considered in this opinion have been approved for addition to foods. This opinion addresses the potential of individual food azo-colours, or their combinations, to cause intolerance and/or allergic reactions in humans after oral exposure, including the nature of symptoms reported and the prevalence of such sensitivities. The potential of azo-colours to cause sensitisation following skin exposure is not addressed in this opinion. 2. Evidence for adverse reactions to individual food colours Since the description of adverse reactions to the synthetic food colour Tartrazine (E 102) over 50 years ago, a number of case reports have been published describing intolerance reactions (TemaNord, 2002). However, most published reports have been inadequately controlled, non-blinded and performed without an appropriate follow-up period to assess the effects of an exclusion diet, and therefore it is uncertain whether the reported adverse reactions were indeed due to oral exposure to Tartrazine. There is a shortage of large, well-controlled intervention studies with defined criteria following double-blind placebo-controlled food challenge (DBPCFC) principles which assessed the (adverse) effects of oral consumption of individual food azo-colours in humans, including Tartrazine. In addition, most of the studies designed to estimate the incidence of Tartrazine intolerance have been conducted on selected patients with intolerance reactions in hospital settings, and no data are available with respect to the prevalence of intolerance to individual azo-colours in a non-selected general population (Elhkhim et al., 2007). Novembre et al. (1992) reported two cases of intolerance reactions to Tartrazine in childen nine and 13 years old involving mainly the central nervous system (headache, migraine, hyperactivity, concentration and learning difficulties, depression) and joints (arthralgias). Intolerance reactions were confirmed with an exclusion diet and a DBPCFC using Tartrazine at doses of 5 and 10 mg. The observed symptoms included urticaria, headache, arthralgias, sneezing and asthenia. Another documented case of intolerance to Tartrazine was reported by Nettis et al. (2003) in one subject who reacted to a DBPCFC after ingestion of 5 mg of Tartrazine with facial oedema and urticaria, abdominal pain and slight hypotension. This was the only subject reacting to the DBPCFC to Tartrazine among the 102 subjects tested with a history of food-induced urticaria and acute angioedema, including two subjects with acetyl salicylic acid (ASA)-sensitivity. The frequency of Tartrazine intolerance was estimated to be <1 % of cases of food-induced urticaria and angioedema. Pestana et al. (2010) challenged 26 atopic adult volunteers with a previous medical history of allergic rhinitis, asthma, urticaria (chronic or acute) and/or hypersensitivity to nonsteroidal anti-inflammatory medications with doses up to 35 mg Tartrazine using a DBPCFC approach. None of the patients had a past history of clinically documented reactions to yellow foods or medications. No significant differences between Tartrazine and placebo groups were observed with respect to cutaneous, respiratory or cardiovascular reactions. The Panel notes that the few documented cases of intolerance reactions to Tartrazine have been observed at doses within the ADI (7.5 mg/kg bw/day). 5

6 Ardern and Ram (2001) conducted a systematic literature review to assess the overall effect of Tartrazine (exclusion or challenge) in the management of asthma. Only DBPCFC trials with Tartrazine and studies on dietary avoidance of Tartrazine versus normal diet were considered. Studies which focused upon allergic asthma were also included. Study quality was assessed and data were independently extracted by two reviewers. Ninety abstracts were found, of which 18 were potentially relevant. Six met the inclusion criteria, but only three presented results in a format that permitted analysis and none could be combined in a meta-analysis. In none of the studies did the Tartrazine challenge or avoidance in the diet significantly modify asthma outcomes. Bhatia (2000) studied consecutive outpatients (May 1996 to April 1998) receiving Tartrazinecontaining psychotropic medications. Subjects showing intolerance reactions to Tartrazine were then exposed to non-tartrazine-containing brands of psychotropic drugs. Of 2210 patients exposed to Tartrazine-containing medications (mostly antidepressants), 83 (3.8 %) developed allergy-like reactions. The symptoms subsided within 24 to 48 hours of stopping the drug. None of the patients showed allergy to non-tartrazine-containing brands. The Panel notes that intolerance to Tartrazine in these patients has not been confirmed using DBPCFC procedures. Two cases of intolerance reactions to oral consumption of Ponceau 4R have been reported. Veien and Krogdhal (1991) describe a 24-year old woman who responded with development of a leukoclastic vasculitis after a DBPCFC with 50 mg of Ponceau 4R. Similarly, Weber et al. (1979) investigated azo colour sensitivities in acetylsalicylic acid (ASA)-sensitive asthmatics. Out of the 43 subjects which were tested with a mixture of azo-dyes (Mix No. l, Amaranth, Sunset Yellow FCF and Ponceau 4R), four were positive on open challenge. When all four subjects were re-tested double-blind with the individual dyes, one patient reacted to Ponceau 4R with bronchoconstriction. This patient underwent a DBPCFC with 20 mg Ponceau 4R twice and reacted on both occasions. Other positive intolerance reactions to provocation tests with Ponceau 4R in ASA-positive and ASA-negative patients suffering from urticaria are less well documented (Lindemayer and Schmidt, 1979). The Panel notes that the challenge doses of Ponceau 4R used in these studies are from 4 to 10 times the ADI (0.7 mg/kg bw/day). A number of studies have been published in which subjects have been challenged with two or more individual azo-dyes. In a DBPCFC clinical study, a group of 43 children with angioedema and/or chronic urticaria and who responded to an additive free diet was challenged with individual food colours hidden in opaque capsules (Supramaniam and Warner, 1986). Ten out of 36 children reacted to Sunset Yellow FCF at a dose of 0.1 mg, 11 out of 43 to Tartrazine at doses of 0.1, 0.5 and 1 mg, four out of 37 to Amaranth at doses of 0.1 mg, none out of 12 to Carmoisine, and one out of 43 to placebo. Reactions included angioedema and urticaria (n=13), urticaria only (n=11), and wheezing (n=4). In a study of 25 patients aged between 1.5 and 12.5 years experiencing allergic reactions after food intake, patients were challenged with individual dyes after a 48-hour avoidance of colours (Ibero et al., 1982). The challenge consisted of Tartrazine, Sunset yellow FCF, Ponceau 4R and Erythrosine, among others. Five subjects reacted to a challenge with Tartrazine, eight subjects to a challenge with Sunset yellow FCF and four subjects reacted to the challenge with Ponceau 4R, all at doses of 1 and 10 mg (5 mg for subjects <15 kg body weight for Ponceau 4R). Lactose was used as placebo. The criteria for scoring the provocations as positive were reproduction of the symptoms that brought the child to the clinic (recurrent urticaria and/or angioedema, dermo-respiratory syndrome) or objective worsening of the pre-existing pattern in atopic dermatitis. In a study by Schultz-Ehrenburg and Gilde (1987) of 90 patients with chronic or chronic relapsing urticaria, 4 % of cases presented with an intolerance which was found to be caused by food additives (benzoates, sorbic acid, Tartrazine and Sunset Yellow FCF). One of the patients who became symptom free during an elimination diet reacted to oral provocation tests with Sunset Yellow FCF and 6

7 with Tartrazine at doses of 10 mg each. It is unclear whether the food additive challenge has been performed under blinded and placebo-controlled conditions. Hypersensitivity to Allura Red AC, Amaranth, Sunset Yellow FCF, Ponceau 4R, and Tartrazine, among other dyes in patients suffering from urticaria or angioedema has been reported in one human study (Mikkelsen et al., 1978). However, the study was uncontrolled and it is not possible to establish whether intolerance reactions occurred due to the food colours rather than to a cross-reaction with the challenge vehicle (soy bean oil). The Panel notes that only few cases of intolerance reactions to Tartrazine and Ponceau 4R, and to a lesser extent to Sunset Yellow FCF and Amaranth have been reported following DBPCFC procedures after exclusion diets. These reactions include urticaria, angioedema, wheezing, and leukoclastic vasculitis. The Panel also notes that no data on sensitivity to Brown FK, Brown HT, Litholrubine BK, Brilliant Black BN, Carmoisine, and Allura Red AC are available, and that no cases of intolerance reactions have been reported after oral exposure to these colours. However, the absence of data on adverse clinical reactions after oral exposure could be due to the lack of clinical awareness of this possibility and subsequent underreporting (EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009a, 2009b, 2009c, 2009d, 2009e, 2010a, 2010b, 2010c, 2010d, 2010e). The mechanism of food colour intolerance is unknown. The incidence of Tartrazine intolerance has been estimated to be <1 % in subjects with food-induced urticaria and angioedema (Nettis et al., 2003). No data are available with respect to the prevalence of intolerance to individual azo-colours in a nonselected general population. The Panel considers that it is unlikely that oral consumption of the individual food colours under consideration would trigger severe adverse reactions in human subjects at the current levels of use. 3. Evidence for adverse reactions to colour mixtures Prevalence estimates of food additive intolerance in adults with atopic symptoms of the respiratory tract and skin are uncertain, but may be less than 0.15 %. In adults and children with reproducible symptoms, such as headache and behavioural/mood changes, the prevalence is estimated to be even lower (0.026 %) (Young et al., 1987). Food additive intolerance is primarily found in atopic children with cutaneous symptoms, where the additive is aggravating an existing disease. The prevalence of food additive intolerance in children aged 5-16 years is about 1-2 % (Young et al., 1987; Fuglsang, 1993, 1994; Madsen, 1994). The frequency of adverse reactions to food additives, and in particular to food colours, in the general population is difficult to assess. A total of 54 patients with an allergic disease randomly recruited in five university hospitals in Korea were enrolled in a DBPCFC with cross-over design (Park et al., 2008). After seven days on a lowfood additive diet, oral challenges were performed with a mixture of seven food additives or placebo. The amount of each food additive in the mixture was 1/10 of the ADI. Five patients had a positive reaction to the food additive mixture but no reactions to the placebo, two patients reacted to both food additives and to the placebo, three patients reacted to the placebo only, and the remaining 44 patients reacted to neither. Urticaria, periorbital oedema, and facial flushing accompanied by itching were the major symptoms. No statistically significant differences were observed between the number of subjects who reacted positively to food additives and the number of subjects who reacted positively to placebo. Results from a DBPCFC study in 153 three-year old children and 144 8/9-year old children by McCann et al. (2007) indicate that exposure to two mixtures of synthetic colours and additives (including Carmoisine, Allura Red, Tartrazine, Ponceau 4R, Sunset Yellow) plus a sodium benzoate preservative increased global hyperactivity aggregate (GHA) score compared to placebo (EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009a, 2009b, 2009c, 2009d, 2009e). 7

8 The Panel notes that only few cases of intolerance reactions to colour mixtures including azo-dyes have been reported in sensitive individuals following DBPCFC procedures after exclusion diets. Intolerance reactions include urticaria, periorbital oedema, facial flushing, as well as increased hyperactivity score in children. The Panel considers that it is unlikely that oral consumption of combinations of the food colours under consideration would trigger severe adverse reactions in human subjects at the current levels of use. CONCLUSIONS There is a shortage of large, well-controlled intervention studies with defined criteria following double-blind placebo-controlled food challenge (DBPCFC) principles which assessed the adverse effects of oral consumption of individual food azo-colours in humans. In addition, most of the studies designed to estimate the incidence of azo-colour intolerance have been conducted in selected patients with intolerance reactions in hospital settings. No data are available with respect to the prevalence of intolerance to individual azo-colours in a non-selected general population. The frequency of Tartrazine intolerance has been estimated to be <1 % in subjects with food-induced urticaria and angioedema. Only few cases of intolerance reactions to Tartrazine and Ponceau 4R, and to a lesser extent to Sunset Yellow FCF and Amaranth, have been reported in sensitive individuals following DBPCFC procedures after exclusion diets. These reactions include urticaria, angioedema, wheezing, and leukoclastic vasculitis. Intolerance reactions to Tartrazine have been observed at doses within the ADI (7.5 mg/kg bw/day), whereas the challenge doses of Ponceau 4R used in the two documented cases of intolerance reactions to this colour ranged from four to 10 times the ADI (0.7 mg/kg bw/day). No data on sensitivity to Brown FK, Brown HT, Litholrubine BK, Brilliant Black BN, Carmoisine, and Allura Red AC are available, and no documented cases of intolerance reactions have been reported after oral exposure to these colours. However, the absence of data on adverse clinical reactions after oral exposure could be due to the lack of clinical awareness of this possibility and subsequent underreporting. Only few cases of intolerance reactions to colour mixtures including azo-dyes have been reported following DBPCFC procedures after exclusion diets. Intolerance reactions include urticaria, periorbital oedema, facial flushing, as well as higher hyperactivity scores in children. The Panel concludes that it is unlikely that oral consumption of the food colours under consideration, either individually or in combination, would trigger severe adverse reactions in human subjects at the current levels of use. REFERENCES Ardern KD and Ram FS, Tartrazine exclusion for allergic asthma. Cochrane Database Syst. Rev. 4: CD Bhatia MS, Allergy to tartrazine in psychotropic drugs. Journal of Clinical Psychiatry, 61, EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009a. Scientific Opinion on the re-evaluation of Allura Red AC (E 129) as a food additive. EFSA Journal, 7(11):1327, 39 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009b. Scientific Opinion on the re-evaluation of Ponceau 4R (E 124) as a food additive. EFSA Journal, 7(11):1328, 39 pp. 8

9 EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009c. Scientific Opinion on the re-evaluation of Sunset Yellow FCF (E 110) as a food additive. EFSA Journal, 7(11):1330, 45 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009d. Scientific Opinion on the re-evaluation of Tartrazine (E 102). EFSA Journal, 7(11):1330, 45 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2009e. Scientific Opinion on the re-evaluation of Azorubine/Carmoisine (E 122) as a food additive. EFSA Journal, 7(11):1332, 40 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010a. Scientific Opinion on the re-evaluation of Brown FK (E 154) as a food additive. EFSA Journal, 8(4):1535, 29 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010b. Scientific Opinion on the re-evaluation of Brown HT (E 155) as a food additive. EFSA Journal, 8(4):1536, 32 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010c. Scientific Opinion on the re-evaluation of Brilliant Black BN (E 151) as a food additive. EFSA Journal, 8(4):1540, 30 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010d. Scientific Opinion on the re-evaluation of Litholrubine BK (E 180) as a food additive. EFSA Journal, 8(5):1586, 26 pp. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2010e. Scientific Opinion on the re-evaluation of Amaranth (E 123) as a food additive. EFSA Journal, 8(7):1649, 42 pp. Elhkim MO, Fanny Héraud F, Bemrah N, Gauchard F, Lorino T, Lambré C, Frémy JM and Jean-Poul JM, New considerations regarding the risk assessment on Tartrazine. An update toxicological assessment, intolerance reactions and maximum theoretical daily intake in France. Regulatory Toxicology and Pharmacology, 47, Fuglsang G, Madsen C, Saval P and Osterballe O, Prevalence of intolerance to food additives among Danish school children. Pediatric Allergy and Immunology, 4, Fuglsang G, Madsen G, Halken S, Jørgensen S, Ostergaard PA and Osterballe O, Adverse reactions to food additives in children with atopic symptoms. Allergy, 49, Ibero M, Eseverri JL, Barroso C and Botey J, Dyes, preservatives and salicylates in the induction of food intolerance and/or hypersensitivity in children. Allergologia et Immunopathologia (Madr), 10, Lindemayer N and Schmidt J, Intolerance to acetylsalicylic and food additives in patients suffering from recurrent urticaria. Wiener Klinische Wochenschrift, 91, Madsen C, Prevalence of food additive intolerance. Human and Experimental Toxicology, 13, McCann D, Barrett A, Cooper C, Crumpler D, Dalen L, Grimshaw K, Kitchin E, Lok K, Porteous L, Prince E, Sonuga-Barke E, O Warner J and Stevenson J, Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomized, doubleblinded, placebo-controlled trial. Lancet, 370, Mikkelsen H, Larsen JC and Tarding F, Archives of Toxicology, Suppl. 1, 141 (as referred to by BIBRA 1982b). Nettis E, Colanardi MC, Ferrannini A and Tursi A, Suspected tartrazine-induced acute urticaria/angioedema is only rarely reproducible by oral challenge. Clinical and Experimental Allergy, 33,

10 Novembre E, Dini L, Bernardini R, Resti M and Vierucci A, Unusual reactions to food additives. Pediatria Medica e Chirurgica, 14, Park HW, Park CH, Park SH, Park JY, Park HS, Yang J, Ahn KM, Kim KH, Oh JW, Kim KE, Pyun BY, Lee HB and Min KU, Dermatologic adverse reactions to 7 common food additives in patients with allergic diseases: A double-blind, placebo-controlled study. Journal of Allergy and Clinical Immunology, 121, Pestana S, Moreira M and Olej B, Safety of ingestion of yellow tartrazine by double-blind placebo-controlled challenge in 26 atopic adults. Allergologia et Immunopathologia (Madr), 38, Schultz-Ehrenburg U and Gilde O, Results of studies in chronic urticaria with special reference to nutritional factors. Zeitschrift für Hautkrankheiten, 62 (Suppl. 1), Supramaniam G and Warner JO, Artificial food additive intolerance in patients with angiooedema and urticaria. Lancet, 2, TemaNord, Food additives in Europe 2000; Status of safety assessments of food additives presently permitted in the EU. TemaNord, 560, Veien and Krogdhal, Cutaneous vasculitis induced by food additives. Acta Dermato- Venereologica, 71, Weber RW, Hoffman M, Raine DA Jr and Nelson HS, Incidence of bronchoconstriction due to aspirin, azo dyes, non-azo dyes, and preservatives in a population of perennial asthmatics. Journal of Allergy and Clinical Immunology, 64, Young E, Patel S, Stoneham M, Rona R and Wilkinson JD, The prevalence of reaction to food additives in a survey population. Journal of the Royal College of Physicians, London, 21,

11 GLOSSARY / ABBREVIATIONS ADI ASA DBPCFC Acceptable daily intake Acetylsalicylic acid Double-blind placebo-controlled food challenge 11